The present invention relates to an active substance for inhibiting the proliferation rate of hepatocytes.
The hepatocyte proliferation rate is normally very low in adult mammals. If, however, part of the liver is removed (partial hepatectomy) in young experimental animals, the proliferation rate suddenly increases by ten to twenty times its original value, dropping back to its normal value after having reached the previous original number of hepatocytes (i.e. after six to eight days). This course of development in liver regeneration (hepatopoiesis) has already been made the object of numerous studies.
Investigation into the molecular mechanism of this loop system resulted in identifying a plurality of growth promoting or inhibiting factors (cf. summary given in: MICHALOPOULOS, G.K., "Liver Regeneration: Molecular Mechanisms of Growth Control"; FASEB, J. 4 (1990), p. 176-187). One such growth promoting factor, which Was isolated in the seventies, is the hormone hepatopoietin (cf/German patent specifications 28 14 981, 29 14 903, 30 37 600).
It was found subsequently that hepatopoietin is contained as well in the ascites of the rat hepatic tumor YOSHIDA AH 130 (S. VOGL et al., J. Hepatol. 11, suppl. 2 (1990) p. 118). According to this, it would appear that this hepatocyte tumor continuously produces its own proliferation hormone. Different studies showed that injection of extracts containing hepatopoietin in mice whose hepatocytes had been injured by galactosamine, results in additional impairment, the lethal dose 50 of galactosamine being thus decreased. Apparently an existing liver damage will be enhanced by hepatocyte proliferation.
It was further found that a factor very similar to hepatopoietin in the blood plasma of patients suffering from hepatic cancer or from chronic hepatitis can be detected (TOPIC, E. et al., Fresenius J. of Anal. Chemistry, 343 (1992), p. 132-133). This is in agreement with the fact that hepatic cancer is closely connected with hepatitis and hepatic cirrhosis (Okuda, K., Hepatol. 15 (1992), p. 948-963).
It is also known that the behaviour of human hepatocytes in tissue culture is very similar to that of animal cells (cf. ISMAIL, T. et al., J. Biol. Chem. 14 (1991), p. 1076-1082).
The search for a growth inhibitor involved in the above described hepatopoiesis loop system resulted in isolating the tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro (N-Ac-SDKP; LOMBARD, M.-N. et al., Cell Tissue Kinet. 23 (1990), p. 99-103). The inhibiting effect, however, has been detected only in adult rats submitted to partial hepatectomy and in young animals (loc. cit.)
From publication DE 40 07 605 A1, the tripeptide Ser-Asp-Lys (corresponding to SDK in the nomenclature used hereinafter, cf. e.g. KARLSON, "Kurzes Lehrbuch der Biochemie", editors Georg Thieme Verlag Stuttgart, 12th edition, 1984, p. 23) is known. According to this, publication SDK inhibits rosette formation due to interaction of human T-cells (leukocytes) and sheep erythrocytes (cf. also THIERRY, J. et al., J. Med. Chem. 33 (1990), p. 2122-2127). Furthermore, an immunomodulating effect of SDK is described, namely stimulation of the humoral response (generation of IgM secreting B-lymphocytes) to red blood cells of sheep in mice.
There are, however, no indications as to any other effects of SDK.